Uncovering inversion formation in the human genome and its impact to disease.

揭示人类基因组中倒位的形成及其对疾病的影响。

基本信息

批准号：
10252936
负责人：
Claudia Carvalho Fonseca
金额：
$ 68.4万
依托单位：
PACIFIC NORTHWEST RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10252936
关键词：
Affect Architecture Biological Biological Process Candidate Disease Gene Chromosomal Instability Chromosome Structures Chromosomes Complex Congenital Abnormality Copy Number Polymorphism Cytogenetics DNA DNA Repair DNA Sequence DNA Sequence Alteration DNA Sequence Rearrangement Data Defect Detection Diagnosis Disease Etiology Event Evolution Frequencies Gene Expression Regulation Generations Genetic Genetic Diseases Genetic Recombination Genome Genome Mappings Genomic Segment Genomics Goals Haplotypes Human Human Biology Human Development Human Genome Individual Infertility Inherited Lead Malignant Neoplasms Mediating Meiosis Methodology Mitosis Mitotic Molecular Molecular Abnormality Optics Pathogenicity Patients Pattern Phase Phenotype Population Genetics Prevalence Primates Procedures Production Role SNP array Sampling Series Structure Subgroup Techniques Testing Validation Variant Work base clinical phenotype comparative genomic hybridization congenital anomaly disease diagnosis ds-DNA genetic disorder diagnosis genome sequencing genomic signature genomic tools high risk nanopore next generation sequencing offspring proband public health relevance reference genome repaired reproductive structural genomics tool trait whole genome

项目摘要

1. Project Summary The relevance of inversions for disease causation, speciation and adaptation, is broadly and prominently recognized although the prevalence is unknown. In humans, de novo inversions are associated with congenital anomalies in ~9.6% of patients. Yet, despite the biological relevance of inversions, their molecular features, formation mechanism, impact to the genomic structure in carriers, as well as their contribution to clinical phenotypes, have not been further explored. Inversions are typically classified as a balanced reciprocal event generated by ectopic recombination, although recent studies reveal a distinct picture whereby inversions originate from mechanisms that concomitantly generate copy number variants (CNVs). Surprisingly, those complex inversions underlie as much as 30% of neurodevelopmental defect-associated CNVs. The hypothesis of this application are: i. inversions are often generated de novo by mechanisms other than ectopic recombination; ii. a relevant fraction of inversions are associated with complex genomic rearrangements (CGRs) often overlooked in sporadic diseases, and iii. inversions are a “hidden” type of structural variation for which contribution to a clinical phenotype has been under assessed due to the lack of appropriate detection tools. These hypotheses will be tested by virtue of the following specific aims: i) to define the relative contributions of distinct DNA repair mechanisms to the formation of inversions; ii) to establish whether CGRs are genomic signature of inversions; and iii) to investigate the scale of contribution of de novo inversions to sporadic diseases. To overcome the limitations of each methodology, a combined strategy of multiple genomic tools will be applied to characterize inversions and associated genomic alterations, consisting of whole genome sequencing (WGS) short-and long-reads, genome mapping classical cytogenetics, array CGH and/or SNP arrays. The results obtained in this application will lead to a more broadly definition for the term inversion, enable estimate of the contribution of mitotic and meiotic DNA repair mechanisms of their formation and reveal the frequency of origin and underlying genomic architecture. Moreover, it will identify candidate genes affected by that structural variant for further genetic and functional validation. In summary, this application will strongly impact our understanding of human biological processes and disease mechanisms associated with inversions with broad implications for diagnosis of birth defects, human development, infertility and cancer. This application will also establish common grounds to bridge studies of rare and common diseases, human evolution and population genetics.

一、项目概要倒转与疾病因果关系、物种形成和适应的相关性广泛且显着尽管在人类中患病率尚不清楚，但从头倒位与先天性相关。然而，尽管倒位具有生物学相关性，但其分子特征，约 9.6% 的患者存在异常。形成机制、对携带者基因组结构的影响及其对临床的贡献倒位通常被归类为平衡的倒数事件。由异位重组产生，尽管最近的研究揭示了一种独特的情况，即倒位令人惊讶的是，这些起源于同时产生拷贝数变异（CNV）的机制。多达 30% 的神经发育缺陷相关 CNV 是由复杂的倒置引起的。该应用的特点是： i. 倒位通常是由异位以外的机制从头产生的。重组； ii. 相关部分的倒位与复杂的基因组重排有关。（CGR）在散发性疾病中经常被忽视，并且 iii. 倒位是一种“隐藏”类型的结构。由于缺乏对临床表型的贡献尚未得到充分评估的变异适当的检测工具将根据以下具体目标进行测试： i) 定义不同 DNA 修复机制对倒位形成的相对贡献 ii) 确定是否 CGR 是倒位的基因组特征；以及 iii) 研究从头倒位的贡献规模为了克服每种方法的局限性，需要采用多种基因组的组合策略。将应用工具来表征倒位和相关的基因组改变，包括全基因组测序 (WGS) 短读长和长读长、基因组作图经典细胞遗传学、阵列 CGH 和/或 SNP 在此应用中获得的结果将为术语反转提供更广泛的定义，使之成为可能。估计有丝分裂和减数分裂 DNA 修复机制对其形成的贡献，并揭示此外，它将识别受其影响的候选基因。进一步遗传和功能验证的结构变体总而言之，该应用将产生强烈影响。我们对与倒转相关的人类生物过程和疾病机制的理解该应用将对出生缺陷、人类发育、不孕症和癌症的诊断产生广泛影响。还建立共同基础来研究罕见疾病和常见疾病、人类进化和人口之间的桥梁遗传学。